Use of nanodispersions in pharmaceutical end formulations

ABSTRACT

A description is given of the use of a nanodispersion, which comprises  
     (a) a membrane-forming molecule,  
     (b) a coemulsifier and  
     (c) a lipophilic component,  
     in pharmaceutical end formulations, the nanodispersion being obtainable by (α) mixing the components (a), (b) and (c) until a homogeneous clear liquid is obtained, and (β) adding the liquid obtained in step (α) to the water phase of the pharmaceutical end formulations, steps (α) and (β) being carried out without any additional supply of energy.  
     The nanodispersions used according to this invention are suitable as transport vehicles for pharmaceutical active agents.

[0001] The present invention relates to the use of nanodispersions inpharmaceutical end formulations, to pharmaceutical end formulationscomprising said nanodispersions and to the different pharmaceutical usesof these end formulations.

[0002] Pharmaceutical end formulations are understood here to meanformulations which comprise, in addition to the basic substancesresponsible for forming the pharmaceutical formulation, other functionalactive agents. These are added to the pharmaceutical base formulationsand can be used for the therapeutic treatment of the nervous system,endocrine system, cardiovascular system, respiratory tract,gastro-intestinal tract, kidneys and efferent urinary tracts, locomotorapparatus, immunological system, skin and mucosae and for the treatmentof infectious diseases.

[0003] In order for these substances to have an effect at the desiredsite, they must be transported to the respective site. To optimise theiravailability at the site of action, many active agents are applied bymeans of so-called carrier and transport vehicles (carrier systems), forexample mixed micelles, liposomes or nanoemulsions (nanoparticles).Examples of such active agents are amphotericin (NeXstar, Sequus, TLC),daunorubicin (NeXstar), doxorubicin (Sequus), inactivated hepatitis Aviruses (Berna), or econazol (Cilag). Applying these active agents bymeans of said carrier systems results in therapeutic advantages such asfewer side-effects or better vaccinal effect.

[0004] Surprisingly, it has now been found that so-callednanodispersions of suitable composition can enhance the effectivity ofmedicinal agents in pharmaceutical end formulations.

[0005] Accordingly, this invention relates to the use of ananodispersion, which comprises

[0006] (a) a membrane-forming molecule,

[0007] (b) a coemulsifier and

[0008] (c) a lipophilic component,

[0009] in pharmaceutical end formulations, the nanodispersion beingobtainable by (α) mixing the components (a), (b) and (c) until ahomogeneous clear liquid is obtained (so-called nanodispersionprephase), and

[0010] (β) adding the liquid obtained in step (α) to the water phase ofthe pharmaceutical end formulations, steps (α) and (β) being carried outwithout any additional supply of energy.

[0011] Step (α) is usually carried out at room temperature, wherenecessary with heating and under normal pressure conditions. Mixing iscarried out using standard stirring apparatus, for example propeller,angled paddle or magnetic agitators, and without using any specialmechanical stirring aids.

[0012] Components (a), (b) and (c) (=step (α)) are mixed in anhydrousmedium, i.e. it is not necessary to add any water.

[0013] Step (β) is carried out by adding the liquid obtained in step(α), the nanodispersion pre-phase, to the water phase of thepharmaceutical end formulations. The particular choice of components(a), (b) and (c) results directly in ultrafine, monodispersenanodispersions. In this case it is possible to forego homogenisationvia nozzle, rotor-stator or ultrasound homogenisers, which is usuallycarried out to convert coarsely disperse or at least heterodispersesystems to fine monodisperse systems. Step (β) is thus characterised bythe absence of high shear or cavitation forces.

[0014] Step (β) is usually carried out at room temperature, which is therange of the respective oil/water phase inversion temperature (PIT).

[0015] The nanodispersions characterised by the process steps (α) and(β) contain particles having an average diameter of <50 nm, typically ofless than 30 nm. The distribution is monodisperse and obeys a Gaussiandistribution.

[0016] It is preferred to use a nanodispersion, which contains,

[0017] (a) as membrane-forming molecules, substances which are suitablefor forming so-called bilayers,

[0018] (b) as coemulsifiers, substances which preferably form OWstructures and,

[0019] (c) as lipophilic component, a lipophilic agent customarily usedfor pharmaceutical preparations.

[0020] The nanodispersion preferably contains as component (a) aphospholipid, a hydrated or partially hydrated phospholipid, alysophospholipid, a ceramide, or mixtures of these compounds,

[0021] wherein

[0022] R₁ is C₁₀-C₂₀acyl;

[0023] R₂ is hydrogen or C₁₀-C₂₀acyl

[0024] R₃ is hydrogen, 2-trimethylamino-1-ethyl, 2-amino-1-ethyl;C₁-C₅alkyl which is unsubstituted or substituted by one or severalcarboxy, hydroxy or amino groups; the inositol or glyceryl group;

[0025] or salts of these compounds.

[0026] C₁₀-C₂₀Acyl is preferably straight-chain C₁₀-C₂₀alkanoylcontaining an even number of carbon atoms and straight-chainC₁₀-C₂₀alkenoyl containing a double bond and an even number of carbonatoms.

[0027] Straight-chain C₁₀-C₂₀alkanoyl containing an even number ofcarbon atoms is, for example, n-dodecanoyl, n-tetradecanoyl,n-hexadecanoyl or n-octadecanoyl.

[0028] Straight-chain C₁₀-C₂₀alkenoyl containing a double bond and aneven number of carbon atoms is, for example, 6-cis- or 6-trans-, 9-cis-or 9-trans-dodecenoyl, -tetradecenoyl, -hexadecenoyl, -octadecenoyl or-eicosenoyl, preferably 9-cis-octa-decenoyl (oleoyl), and also9,12-cis-octadecadienoyl or 9,12,15-cis-octadecatrienoyl.

[0029] A phospholipid of formula (1), wherein R₃ is2-trimethylamino-1-ethyl, is referred to by the trivial name lecithin,and a phospholipid of formula (1), wherein R₃ is 2-amino-1-ethyl, by thetrivial name cephalin. Suitable are, for example, naturally occurringcephalin or lecithin, e.g. cephalin or lecithin from soybeans or chickeneggs with different or identical acyl groups, or mixtures thereof.

[0030] The phospholipid of formula (1) may also be of synthetic origin.The expression “synthetic phospholipid” is used to define phospholipidshaving uniform composition with respect to R₁ and R₂. Such syntheticphospholipids are preferably the lecithins and cephalins defined above,wherein the acyl groups R₁ and R₂ have a defined structure and which arederived from a defined fatty acid having a degree of purity greater thanabout 95%. R₁ and R₂ may be identical or different and unsaturated orsaturated. Preferably, R₁ is saturated, for example n-hexadecanoyl, andR₂ is unsaturated, for example 9-cis-octadecenoyl (oleoyl).

[0031] The expression “naturally occurring” phospholipid defines aphospholipid that does not have a uniform composition with respect to R₁and R₂. Such natural phospholipids are likewise lecithins and cephalins,wherein the acyl groups R₁ and R₂ are derived from naturally occurringfatty acid mixtures.

[0032] The requirement “substantially pure” phospholipid of formula (1)defines a degree of purity of more than 90% by weight, preferably ofmore than 95% by weight of the phospholipid of formula (1), which can bedemonstrated by means of suitable determination methods, for example bypaper chromatography, thin-layer chromatography, by HPLC or by means ofenzymatic colour testing.

[0033] In a phospholipid of formula (1), R₃ defined as C₁-C₄alkyl is,for example, methyl or ethyl. Methyl is preferred.

[0034] R₃ defined as C₁-C₅alkyl substituted by one or several carboxy,hydroxy or amino groups is, for example, 2-hydroxyethyl,2,3-dihydroxy-n-propyl, carboxymethyl, 1- or 2-carboxyethyl,dicarboxymethyl, 2-carboxy-2-hydroxyethyl or3-carboxy-2,3-dihydroxy-n-propyl, 3-amino-3-carboxy-n-propyl or2-amino-2-carboxy-n-propyl, preferably 2-amino-2-carboxyethyl.

[0035] Phospholipids of formula (1) containing these groups can bepresent in salt form, for example as sodium or potassium salt.

[0036] Phospholipids of formula (1), wherein R₃ is the inositol orglyceryl group, are known by the names phosphatidylinositol andphosphatidylglycerol.

[0037] The acyl radicals in the phospholipids of formula (1) are alsocustomarily known by the names given in brackets:

[0038] 9-cis-dodecenoyl (lauroleoyl), 9-cis-tetradecenoyl(myristoleoyl), 9-cis-hexadecenoyl (palmitoleoyl), 6-cis-octadecenoyl(petroseloyl), 6-trans-octadecenoyl (petroselaidoyl), 9-cis-octadecenoyl(oleoyl), 9-trans-octadecenoyl (elaidoyl), 9,12-cis-octadecadienoyl(linoleoyl), 9,12,15-cis-octadecatrienoyl (linolenoyl),11-cis-octadecenoyl (vaccenoyl), 9-cis-eicosenoyl (gadoleoyl),5,8,11,14-cis-eicosatetraenoyl (arachidonoyl), n-dodecanoyl (lauroyl),n-tetradecanoyl (myristoyl), n-hexadecanoyl (palmitoyl), n-octadecanoyl(stearoyl), n-eicosanoyl (arachidoyl), n-docosanoyl (behenoyl),n-tetracosanoyl (lignoceroyl).

[0039] A salt of the phospholipid of formula (1) is preferablypharmaceutically acceptable. Salts are defined by the existence ofsalt-forming groups in the substituent R₃ and by the free hydroxyl groupat the phosphorus atom. The formation of internal salts is alsopossible. Alkali metal salts, especially the sodium salt, are preferred.

[0040] In a particularly preferred embodiment of this invention,purified lecithin from soybeans of the quality LIPOID S 100 or S 75, ora lecithin defined in the monograph USP23/NF 18, is used.

[0041] Component (a) is preferably used in a concentration of about 0.1to 30% by weight, based on the total weight of components (a), (b) and(c).

[0042] Component (b) is preferably an emulsifier or emulsifier mixturesforming the preferred O/W structures.

[0043] Especially preferred emulsifiers are

[0044] alkali, ammonium and amine salts of fatty acids. Examples of suchsalts are the lithium, sodium, potassium, ammonium, triethylamine,ethanolamine, diethanolamine or triethaolamine salts. It is preferred touse the sodium, potassium or ammonium (NR1R2R3) salts, wherein R₁, R₁and R₁ are each independently of one another hydrogen, C₁-C₄alkyl orC₁-C₄hydroxyalkyl.

[0045] saturated and unsaturated alkyl sulfates, such as sodiumdocecylsulfate and alkane-sulfonates such as sodium dodecanesulfonate;

[0046] salts of colic acid, such as sodium cholate, sodium glycocholateand sodium taurocholate;

[0047] invert soaps (quats), such as zetylpyridinium chloride;

[0048] partial fatty acid esters of sorbitan, such as sorbitanmonolaurate;

[0049] sugar esters of fatty acids, such as sucrose monolaurate;

[0050] alkylglucosides, such as n-octylglucoside or n-dodecylglucoside;

[0051] alkylmaltosides, such as n-dodecylmaltoside;

[0052] fatty acid partial glycerides, such as lauric acid monoglyceride;

[0053] C₈-C₁₈betaines, C₈-C₂₄alkylamido-C₁-C₄alkylenebetaines andC₈-C₁₈sulfobetaines;

[0054] proteins, such as casein;

[0055] polyglycerol esters of fatty acids;

[0056] propylene glycol esters of fatty acids;

[0057] lactates of fatty acids, such as sodium stearoyllactyl-2-lactate;

[0058] fatty alcohol phosphorates.

[0059] Emulsifiers of the polyoxyethylene type are very particularlypreferred. Examples of such emulsifiers are:

[0060] polyethoxylated sorbitan fatty acid esters, such as polysorbate80;

[0061] polyethoxylated fatty alcohols, such as oleth-20;

[0062] polyethoxylated fatty acids, such as polyoxyl 20 stearate;

[0063] polyethoxylated vitamin E derivatives, such as vitamin Epolyethylene glycol 1000 succinate;

[0064] polyethoxylated lanoline and lanoline derivatives, such aslaneth-20;

[0065] polyethoxylated fatty acid partial glycerides, such as diethyleneglycol monostearate;

[0066] polyethoxylated alkylphenols, such as ethylphenolpoly(ethyleneglycol ether)11;

[0067] sulfuric acid semiester polyethoxylated fatty alcohols and theirsalts, such as C₁₂-C₁₄-fatty alcohol ether sulfate-2 EO-sodium salt;

[0068] polyethoxylated fatty amines and fatty acid amides;

[0069] polyethoxylated carbon hydrates

[0070] block polymers of ethylene oxide and propylene oxide, such aspoloxamer 188.

[0071] Component (b) is present in the nanodispersion used according tothis invention in a concentration of about 1 to about 50% by weight,based on the total weight of the components (a), (b) and (c).

[0072] Component (c) is preferably a natural or synthetic or a partiallysynthetic di- or triglyceride, a mineral oil, silicone oil, wax, fattyalcohol, guerbet alcohol or the ester thereof, a therapeutic oil, alipophilic pharmaceutical active agent or a mixture of these substances.

[0073] Active agents suitable for pharmaceutical application are to befound, inter alia, in Arzneimittelkompendium 1997. Examples of suitableactive agents are:

[0074] analgesics, antacids/ulcus treatments, antiallergic agents,antianemic drugs, antidepressants, antidiabetic agents, antidiarrhealagents, antidotes/addiction-combating agents/emetics,anti-emetics/antivertiginosa, antiepileptic agents, antihemorrhagicagents, anti-hypertensives, antihypotonic agents, antiinfectives,anticoagulants, antirheumatic agentsl anti-inflammatory agents, appetitedepressants, beta blockers, bronchodilators, cholinergic agents,dermatological agents, disinfectants, diagnostic agents, dieteticagents, diuretics, blood flow stimulants, gastroenterological agents,gout remedies, influenza remedies, gynecological agents,antihemorrhoidal agents, hormones, antitussives, hypnotics,immunological agents, intravenous infusions, cardiac remedies,contraceptives, contrast media, adrenocortical steroids, laxatives,liver and gall therapeutic agents, lipid metabolism preparations, localanesthetics, migraine analgesics, mineral metabolism preparations,muscle relaxants, narcotics, neuroleptic agents, odontological agents,ophthalmic agents, otorhinolaryngological agents (ORL), anti-parkinsondrugs, psychostimulants, sedatives, spasmolytic agents,tonics/roborants, tranquilisers, anti-tuberculosis drugs, urologicalagents, preparations for varicose veins, consolidants and zytostaticagents.

[0075] Component (c) is present in the nanodispersions used according tothis invention in a concentration of preferably 0.1 to 80% by weight,based on the total weight of components (a), (b) and (c).

[0076] The nanodispersion used according to this invention optionallycomprises as facultative component (d) a solubiliser, preferably aC₂-C₈alcohol, such as ethanol or propylene glycol.

[0077] A nanodispersion containing the components (a), (b), (c) andoptionally (d) is distinguished by favourable phase properties of thesolubilised functional pharmaceutical agent. Thus if there isopalescence and transparency in incident light, only a very slightturbidity shows that the dispersion is physically still different fromthe ideal state of a genuine molecular solution. Electron microscopicimages show that a population of more than 98% is present in a Gaussiandistribution as a suspension of particles (nanoparticles) having aparticle size of less than about 50 nm, typically of less than about 30nm. However, these distinctions from a genuine solution can be toleratedbecause of the particularly good homogeneity properties of thedispersion which can be evidenced, for example, by a surprisingly highstorage stability, e.g. no separation after storing for several monthsat temperatures of up to room temperature (stability to be expected byextrapolation: more than two years).

[0078] Laser light scattering measurements and electron microscopicanalysis (Cryo-TEM) confirm the very small size and excellenthomogeneity of the nanoparticles present in the nano-dispersion.

[0079] Another advantage of the nanodispersions used according to thisinvention is that they are easy to prepare.

[0080] The nanodispersions characterised by claim 1 are used accordingto this invention for pharmaceutic end formulations.

[0081] This invention also relates to the so-called nanodispersionprephase characterised in step (α), which is obtainable by mixing thecomponents

[0082] (a) membrane-forming molecules,

[0083] (b) coemulsifier,

[0084] (c) lipophilic component and, optionally,

[0085] (d) a C₂-C₈alcohol, preferably propylene glycol and, morepreferably, ethanol until a homogeneous clear liquid is obtained, mixingbeing carried out in anhydrous medium.

[0086] In accordance with this invention, the nanodispersion prephase orthe nanodispersion is used directly for pharmaceutical end formulations.

[0087] The pharmaceutical end formulations are preferably liquid,semisolid or solid preparations.

[0088] Examples of liquid pharmaceutical end formulations are injectablesolutions, infusion solutions, drops, sprays, aerosols, emulsions,lotions, suspensions, drinking solutions, gargles and inhalants.

[0089] Examples of semisolid pharmaceutical end formulations areointments, creams (O/W emulsions), rich creams (W/O emulsions), gels,lotions, foams, pastes, suspensions, ovula, plasters, includingtransdermal systems.

[0090] Examples of solid pharmaceutical end formulations are tablets,coated tablets, capsules, granules, effervescent granules, effervescenttablets, lozenges, sucking and chewing tablets, suppositories, implants,lyophilisates, adsorbates or powders.

[0091] This invention also relates to these end formulations.

[0092] The end formulations contain the nanodispersion in aconcentration of 0.01 to 100 by weight, preferably of 0.05 to 20 byweight and, more preferably, of 0.1 to 10% by weight.

[0093] To prepare liquid and semisolid pharmaceutical end products(Examples 20 to 29), the nanodispersions are incorporated into theaqueous component of the end product. It is also possible to add insteadof the nanodispersion the corresponding nanodispersion prephase to thewater phase of the pharmaceutical end formulation. The nanodispersionprephase is added to the water phase with stirring and preferably at atemperature in the range of the respective oil/water phase inversiontemperature (PIT).

[0094] Solid pharmaceutical end products, such as tablets (Example 30),effervescent tablets, coated tablets, granules, effervescent granulesand plasters, are coated or loaded with nanodispersions by spraying ordrenching. In certain cases it is advantageous to admix the dehydratedform of the nanodispersion to the solid mixture. The nanodispersion isusually dehydrated by freeze- or spray-drying in the presence ofcustomary excipients. Capsules, in particular elastic gelatin capsules,can also be loaded with the nanodispersion prephase (Example 31).

[0095] Matrix- or membrane-controlled pharmaceutical applicationsystems, such as oros capsules, transdermal systems, injectablemicrocapsules or implants, are loaded by conventional methods withnanodispersions. Oros capsules can also be loaded with thenanodispersion prephase.

[0096] In addition to the excipients for providing the pharmaceuticaldosage form, the pharmaceutical end formulation can also contain othercomponents, for example stabilisers, preservatives such as parabenes,antioxidants, and aromatics, fragrances or colourants.

[0097] The pharmaceutical end formulations are preferably used for thetherapeutic treatment of the nervous system, endocrine system,cardiovascular system, respiratory tract, gastro-intestinal tract,kidneys and efferent urinary tracts, locomotor apparatus, immunologicalsystem, skin and mucosae as well as for the treatment of infectiousdiseases, tumours and vitamin and mineral deficiency diseases.

[0098] The novel pharmaceutical end formulation is preferably appliedepicutaneously, buccally, lingually, sublingually, enterally(=perorally), rectally, nasally, pulmonally, per inhalationem,conjunctivally, intravaginally, intraurethrally, intracardially,intraarterially, intravenously, intralumbally, intrathecally,intraarticularly, intracutaneously, subcutaneously, intramuscularly andintraperitoneally.

[0099] In the following Examples, percentages are by weight. Unlessotherwise stated, amounts of compounds used are based on the puresubstance.

[0100] Working Examples for Nanodispersion Prephases

EXAMPLE 1

[0101] Miglyol 812 Nanodispersion Prephase soybean lecithin 17.30%polysorbate 80 34.00% miglyol 812 34.50% ethanol 14.20%

[0102] Preparation: Miglyol 812 and polysorbate 80 are mixed. Thesoybean lecithin is dissolved in ethanol and added to this mixture,resulting in a homogeneous clear liquid.

EXAMPLE 2

[0103] Miglyol 812 Nanodispersion Prephase soybean lecithin 17.30%oleth-20 34.00% miglyol 812 34.50% ethanol 14.20%

[0104] Preparation: Miglyol 812 and oleth-20 are mixed, with heating.The soybean lecithin is dissolved in ethanol and added to this mixture,resulting in a homogeneous clear liquid.

EXAMPLE 3

[0105] Miglyol 812 Nanodispersion Prephase soybean lecithin 17.30%laneth-20 34.00% miglyol 812 34.50% ethanol 14.20%

[0106] Preparation: Miglyol 812 and Laneth-20 are mixed, with heating.The soybean lecithin is dissolved in ethanol and added to this mixture,resulting in a homogeneous clear liquid.

EXAMPLE 4

[0107] Miglyol 812 Nanodispersion Prephase soybean lecithin 17.30%vitamin E polyethylene glycol succinate 34.00% (vitamin E TPGS, Eastman)miglyol 812 34.50% ethanol 14.20%

[0108] Preparation: Miglyol 812 and vitamin E polyethylene glycolsuccinates are mixed, with heating. The soybean lecithin is dissolved inethanol and added to this mixture, resulting in a homogeneous clearliquid.

EXAMPLE 5

[0109] Vitamin E Acetate Nanodispersion Prephase soybean lecithin 9.00%polysorbate 80 34.00% vitamin E acetate 36.60% miglyol 812 13.00%ethanol 7.40%

[0110] Preparation: Miglyol 812, vitamin E acetate and polysorbate 80are mixed. The soybean lecithin is dissolved in ethanol and added tothis mixture, resulting in a homogeneous clear liquid.

EXAMPLE 6

[0111] Vitamin A Palmitate Nanodispersion Prephase soybean lecithin17.30% polysorbate 80 34.00% vitamin A palmitate (1.7 × 10⁶ IU/g) 4.50%miglyol 812 30.00% ethanol 14.20%

[0112] Preparation: Vitamin A palmitate, miglyol 812 and polysorbate 80are mixed. The soybean lecithin is dissolved in ethanol and added tothis mixture, resulting in a homogeneous clear liquid.

EXAMPLE 7

[0113] Tridecyl Salicylate Nanodispersion Prephase soybean lecithin11.00% polysorbate 80 26.00% tridecyl salicylate 40.50% miglyol 81213.50% ethanol 9.00%

[0114] Preparation: Tridecyl salicylate, miglyol 812 and polysorbate 80are mixed. The soybean lecithin is dissolved in ethanol and added tothis mixture, resulting in a homogeneous clear liquid.

[0115] Working Examples for Nanodispersions

EXAMPLE 8

[0116] Miglyol 812 Nanodispersion soybean lecithin 1.73% polysorbate 803.40% miglyol 812 3.45% ethanol 1.42% 10 mm phosphate buffer, pH 6 ad100.00%

[0117] Preparation: The water phase (e.g. 90 kg) is placed, withstirring (e.g. magnetic agitator), at 50° C. in a vessel. The liquidnanodispersion prephase of Example 1 (e.g. 10 kg) is added to the waterphase with stirring (e.g. with a magnetic agitator).

EXAMPLE 9

[0118] Miglyol 812 Nanodispersion soybean lecithin 1.73% oleth-20 3.40%miglyol 812 3.45% ethanol 1.42% 10 mm phosphate buffer, pH 6 ad 100.00%

[0119] The nanodispersion is prepared in analogy to the procedure ofExample 8.

EXAMPLE 10

[0120] Migylol 812 Nanodispersion soybean lecithin 1.73% laneth-20 3.40%miglyol 812 3.45% ethanol 1.42% 10 mm phosphate buffer, pH 6 ad 100.00%

[0121] The nanodispersion is prepared in analogy to the procedure ofExample 8.

EXAMPLE 11

[0122] Miglyol 812 Nanodispersion soybean lecithin 1.73% vitamin Epolyethylene glycol succinate 3.40% (vitamin E TPGS, Eastman) miglyol812 3.45% ethanol 1.42% 10 mm phosphate buffer, pH 6 ad 100.00%

[0123] The nanodispersion is prepared in analogy to the procedure ofExample 8.

EXAMPLE 12

[0124] Dexpanthenol Nanodispersion dexpanthenol 5.00% soybean lecithin1.73% polysorbate 80 3.40% miglyol 812 3.45% ethanol 1.42% 10 mmphosphate buffer, pH 6 ad 100.00%

[0125] Preparation: The water phase comprising dexpanthenol (e.g. 90 kg)is placed, with stirring (e.g. magnetic agitator), at 50° C. in avessel. The liquid nanodispersion prephase of Example 1 (e.g. 10 kg) isadded to the water phase with stirring (e.g. magnetic agitator).

EXAMPLE 13

[0126] Dexpanthenol Nanodispersion dexpanthenol 5.00% soybean lecithin1.73% polysorbate 80 3.40% miglyol 812 3.45% ethanol 1.42% 10 mmphosphate buffer, pH 7.4 ad 100.00%

[0127] The nanodispersion is prepared in analogy to the procedure ofExample 12.

EXAMPLE 14

[0128] Vitamin E Acetate Nanodispersion vitamin E acetate 2.00% soybeanlecithin 0.49% polysorbate 80 1.86% miglyol 812 0.71% ethanol 0.63% 10mm phosphate buffer, pH 6 ad 100.00%

[0129] Preparation: The water phase (e.g. 94.54 kg) is placed, withstirring (e.g. magnetic agitator), at 50° C. in a vessel. The liquidnanodispersion prephase of Example 5 (e.g. 5.46 kg) is added to thewater phase with stirring (e.g. magnetic agitator).

EXAMPLE 15

[0130] Vitamin E Acetate Nanodispersion vitamin E acetate 2.00% soybeanlecithin 0.49% polysorbate 80 1.86% miglyol 812 0.71% ethanol 0.63% 10mm phosphate buffer, pH 7.4 ad 100.00%

[0131] The nanodispersion is prepared in analogy to the procedure ofExample 14.

EXAMPLE 16

[0132] Vitamin A Palmitate Nanodispersion vitamin A palmitate (1.7 × 10⁶IU/g) 0.45% soybean lecithin 1.73% miglyol 812 3.00% polysorbate 803.40% ethanol 1.42% 10 mm phosphate buffer, pH 6 ad 100.00%

[0133] The nanodispersion is prepared in analogy to the procedure ofExample 8.

EXAMPLE 17

[0134] Vitamin A Palmitate Nanodispersion vitamin A palmitate (1.7 × 10⁶IU/g) 0.45% soybean lecithin 1.73% miglyol 812 3.00% polysorbate 803.40% ethanol 1.42% 10 mm phosphate buffer, pH 7.4 ad 100.00%

[0135] The nanodispersion is prepared in analogy to the procedure ofExample 8.

EXAMPLE 18

[0136] Solcoseryl Nanodispersion solcoseryl 1.00% soybean lecithin 1.73%polysorbate 80 3.40% miglyol 812 3.45% ethanol 1.42% 10 mm phosphatebuffer, pH 6 ad 100.00%

[0137] Preparation: The water phase comprising solcoseryl (e.g. 90 kg)is placed, with stirring (e.g. magnetic agitator), at 50° C. in avessel. The liquid nanodispersion prephase of Example 1 (e.g. 10 kg) isadded to the water phase with stirring (e.g. magnetic agitator).

EXAMPLE 19

[0138] Tridecyl Salicylate Nanodispersion tridecyl salicytate 4.05%soybean lecithin 1.10% polysorbate 80 2.60% miglyol 812 1.35% ethanol0.90% 10 mm phosphate buffer, pH 6 ad 100.00%

[0139] Preparation: The water phase (e.g. 90 kg) is placed, withstirring (e.g. magnetic agitator), at 50° C. in a vessel. The liquidnanodispersion prephase of Example 7 (e.g. 10 kg) is added to the waterphase with stirring (e.g. magnetic agitator).

[0140] The particle sizes and particle size distributions ofnanodispersions are compiled in the following Table 1. TABLE 1 ParticleStandard Particle diameter¹ deviation size Nanodispersion [nm] [nm]distribution migylol 812 nanodispersion 13.8 4.1 Gauss Example 8dexpanthenol nanodispersion 19.7 5.4 Gauss Example 12 vitamin E acetatenanodispersion 12.2 5.5 Gauss Example 14 vitamin A palmitatenanodispersion 10.1 3.9 Gauss Example 16 solcoseryl nanodispersion 7.33.4 Gauss Example 18 tridecyl salicylate nanodispersion 16.3 6.6 GaussExample 19

[0141] As the following Tables show, nanodispersions also have excellentstorage stability:

[0142] Dexpanthenol Nanodispersion (Example 12) TABLE 2 Storageconditions Standard Duration Temperature Diameter² deviationDexpanthenol³ [months] [° C.] pH [nm] [nm] content [%] 0 6.1 19.7 5.45.37 3 7 6.1 19.0 6.7 5.36 25 6.1 22.2 7.7 5.32 40 6.3 36.6 14.2 5.23 67 6.1 20.8 7.3 5.30 25 6.2 24.1 9.2 5.26 40 6.4 35.4 17.7 5.20

[0143] Vitamin E Acetate Nanodispersion (Example 14) TABLE 3 Storageconditions Standard Vitamin E Duration Temperature Diameter⁴ deviationacetate⁵ [months] [° C.] pH [nm] [%] content [%] 0 6.1 12.2 5.5 2.04 3 76.1 16.1 6.6 2.02 25 6.1 17.5 7.0 2.04 40 6.0 15.4 6.8 2.01 6 7 6.1 17.06.9 2.04 25 6.0 17.6 7.2 2.03 40 6.0 20.8 7.9 2.02

[0144] Working Examples for Pharmaceutical End Formulations withNanodispersions or Nanodispersion Prephases

EXAMPLE 20

[0145] Dexpanthenol 5% Controlled Dosage Non-Aerosol SprayNanodispersion according to Example 12 100.00%

[0146] The preparation has good anti-inflammatory action.

EXAMPLE 21

[0147] Dexpenthanol Vitamin E Acetate Lotion cera emulsificanscetomacrogolis 3.0% oleylium oleinicum 6.0% propylene glycolum 3.0%nanodispersion of Example 12 10.0% nanodispersion of Example 14 10.0%aqua purificata ad 100.0%

[0148] The preparation has good anti-inflammatory action.

EXAMPLE 22

[0149] Dexpanthenol 2.5% Eye Drops mannitol 4.70% nanodispersion ofExample 13 50.00% 10 mm phosphate buffer, pH 7.4 ad 100.00%

[0150] The preparation has a good anti-inflamatory action.

EXAMPLE 23

[0151] Vitamin A Palmitate 0.1% cream cetyl alcohol 10.00% hydrogenatedgroundnut oil 20.00% polysorbate 60 5.00% propylene glycol 20.00%phenoxyethanol 0.50% nanodispersion of Example 16 23.00% aqua purificataad 100.00%

[0152] The preparation has good vitamin A action.

EXAMPLE 24

[0153] Vitamin A Palmitate 0.1% Aerosol sodium EDTA 0.05% mannitol 4.70%nanodispersion of Example 17 23.00% 10 mm phosphate buffer, pH 7.4 ad100.00%

[0154] The preparation has good vitamin A action.

EXAMPLE 25

[0155] Tridecyl Salicylate 1.0% Ointment citric acid 0.75% ammoniasolution 0.09% medium-chain triglyceride 5.00% unguentum alcoholum lanaeaquosum DAB 9 40.00% nanodispersion of Example 19 25.00% aqua purificataad 100.00%

[0156] The preparation has good keratinolytic action.

EXAMPLE 26

[0157] Solcoseryl 0.5% Hydropel sodium carboxymethylcellulose 450 cP3.50% nanodispersion of Example 18 50.00% aqua purificata ad 100.00%

[0158] The preparation is pleasantly cooling and has good antiphlogisticaction.

EXAMPLE 27

[0159] Solcoseryl 1.0% Controlled Dosage Non-Aerosol SprayNanodispersion of Example 18 100.00%

[0160] The preparation has good anti-inflammatory action.

EXAMPLE 28

[0161] Vitamin E Acetate Drink Ampoules citric acid 0.40% glucose 7.50%aroma 0.50% nanodispersion of Example 14 50.00% aqua purificata ad100.00%

[0162] The preparation has good antioxidative action.

EXAMPLE 29

[0163] Vitamin E Acetate Injectable Solution mannitol 4.70%nanodispersion of Example 15 75.00% 10 mm phosphate buffer, pH 7.4 ad100.00%

EXAMPLE 30

[0164] Vitamin E Acetate Tablets hydroxypropylmethylcellulose 15.00%(methocel E4M CR grade) magnesium stearate 0.70% vitamin E acetate⁶1.00% lactose ad 100.00%

[0165] The preparation has good antioxidative action.

EXAMPLE 31

[0166] Vitamin E Acetate Elastic Gelatin Capsules

[0167] Elastic gelatin capsules are filled with the nanodispersionprephase of Example 5. The preparation has good antioxidative action.

What is claimed is
 1. A method of preparing a pharmaceutic end formulation using a nanodispersion, which comprises (a) a membrane-forming molecule, (b) a coemulsifier and (c) a lipophilic component, by (α) mixing the components (a), (b) and (c) until a homogeneous clear liquid is obtained (so-called nanodispersion prephase), and (β) adding the liquid obtained in step (α) to the water phase of the pharmaceutical end formulations, steps (α) and (β) being carried out without any additional supply of energy.
 2. A Method according to claim 1, which is characterised in that step (a) is carried out in anhydrous medium.
 3. A Method according to claim 1, which is characterised in that step (α) is carried out without homogenisation.
 4. A Method according to claim 1, which is characterised in that the particles in the nanodispersion have an average diameter of <50 nm.
 5. A Method according to claim 1, which is characterised in that the nanodispersion comprises, (a) as membrane-forming molecules, substances which are suitable for forming bilayers, (b) as coemulsifiers, substances which preferably form O/W structures and, (c) as lipophilic component, a lipophilic active agent.
 6. A Method according to claim 1, which is characterised in that the nanodispersion comprises as component (a) a phospholipid, a hydrated or partially hydrated phospholipid, a lysophospholipid, a ceramide or mixtures thereof.
 7. A Method according to claim 6, which is characterised in that the component (a) is present in the nanodispersion in a concentration of 0.1 to 30% by weight, based on the total weight of the components (a), (b) and (c).
 8. A Method according to claim 1, which is characterised in that the nanodispersion comprises as component (b) an emulsifier of the polyoxethylene type, saturated and unsaturated C₈-C₁₈alkylsulfates, the alkali metal, ammonium or amine salts of C₈-C₂₀fatty acids, C₈-C₂₀alkanesulfonates, fatty alcohol phosphorates, the salts of colic acid, invert soaps (quats); partial fatty acid esters of sorbitan, sugar esters of fatty acids, fatty acid partial glycerides, alkylmaltosides, alkylglucosides, C₈-C₁₈betaines, C₈-C₁₈sulfobetaines or C₈-C₂₄alkylamido-C₁-C₄alkylenebetaines, proteins, polyglycerol esters of fatty acids, propylene glycol esters of fatty acids, lactates of fatty acids or a mixture of these substances.
 9. A Method according to claim 8, which is characterised in that the nanodispersion comprises as component (b) at least one emulsifier of the polyoxyethlene type.
 10. A Method according to claim 9, which is characterised in that the nanodispersion comprises as component (b) polyethoxylated sorbitan fatty acid esters, polyethoxylated fatty alcohols, polyethoxylated fatty acids, polyethoxylated vitamin E derivatives, polyethoxylated lanolin and the derivatives thereof, polyethoxylated fatty acid partial glycerides, polyethoxylated alkylphenols, sulfuric acid semiesters, polyethoxylated fatty alcohols and the salts thereof, polyethoxylated fatty amines and fatty acid amides, polyethoxylated carbohydrates, block polymers of ethylene oxide and propylene oxide.
 11. A Method according to claim 1, which is characterised in that component (b) is present in the nanodispersion used according to this invention in a concentration of 1 to 50% by weight, based on the total weight of the components (a), (b) and (c).
 12. A Method according to claim 1, which is characterised in that the nanodispersion comprises as component (c) a natural or synthetic or a partially synthetic di- or triglyceride, mineral oil, silicone oil, wax, fatty alcohol, guerbet alcohol or the ester thereof, a lipophilic functional pharmaceutical active agent or a mixture of these substances.
 13. A Method according to claim 1, which is characterised in that component (c) is present in the nanodispersion used according to this invention in a concentration of 0.1 to 80% by weight, based on the total weight of the components (a), (b) and (c).
 14. A Method according to claim 1, which is characterised in that the nanodispersion comprises as component (d) a C₂-C₈alcohol.
 15. A Method according to claim 1, which is characterised in that the pharmaceutical end formulation is a liquid, semisolid or solid preparation.
 16. A pharmaceutical liquid end formulation in the form of an injectable solution, infusion solution, drops, spray, aerosol, emulsion, lotion, suspension, drinking solution, gargle or inhalant, which comprises a nanodispersion as defined in claim
 1. 17. A pharmaceutical semisolid end formulation in the form of an ointment, cream (O/W emulsions), rich cream (W/O emulsions), gel, lotion, foam, paste, suspension, ovula or plaster, which comprises a nanodispersion as defined in claim
 1. 18. A pharmaceutical solid end formulation in the form of a tablet, coated tablet, capsule, granules, effervescent granules, effervescent tablet, lozenge, sucking and chewing tablet, suppositories, implant, lyophilisate, adsorbate or powder, which comprises a nanodispersion as defined in claim
 1. 19. A matrix- or membrane-controlled pharmaceutical application system in the form of an oros capsule, transdermal system, injectable microcapsule, which comprises a nanodispersion as defined in claim
 1. 20. A pharmaceutical end formulation according to claim 16, wherein the nanodispersion is present in the aqueous phase.
 21. A pharmaceutical end formulation according to claim 16, wherein the nanodispersion is present in the aqueous phase in a concentration of 0.01 to 100% by weight.
 22. A pharmaceutical end formulation according to claim 18, wherein the nanodispersion is present per se.
 23. A pharmaceutical end formulation according to claim 16, wherein the nanodispersion prephase is present per se.
 24. A pharmaceutical end formulation according to claim 18, wherein the nanodispersion is present in dehydrated form.
 25. A nanodispersion prephase, which is obtained by mixing the components (a) membrane-forming molecule, (b) coemulsifier and (c) lipophilic component until a homogeneous clear liquid is obtained, mixing being carried out in anhydrous medium.
 26. A nanodispersion prephase according to claim 25, which is characterised in that mixing is carried out without any additional supply of energy.
 27. A nanodispersion, which comprises (a) a membrane-forming molecule, (b) a coemulsifier and (c) a lipophilic component, which is obtainable by (α) mixing the components (a), (b) and (c) until a homogeneous clear liquid is obtained, and (β) adding the liquid obtained in step (α) to the water phase, steps (α) and (β) being carried out without additional supply of energy. 